At the time of sexual transmission, HIV must infect a sufficient number of susceptible target cells within the genital or anal mucosa in order to establish systemic infection. The details of this process have been difficult to ascertain, particularly in humans, but may contain the key to improving biomedical HIV prevention. In this study we aim to better characterize the biological determinants in the host that might influence susceptibility to HIV infection at the time of HIV transmission, with a goal of deriving a strategy that can block HIV infection at the mucosal level. In particular, we will focus our efforts on understanding the role of the gut homing integrin ?4?7 and its ligands in HIV acquisition and disease progression. This is in part because regardless of the route of infection, HIV rapidly localizes to gut tissues within the first few weeks post-infection, and the gut also experiences the most severe depletion of CD4+ T cells throughout the course of infection. Moreover, ?4?7 binds and signals through HIV gp120 molecules in a way that mimics its natural receptor, MAdCAM-1. This ?4?7-binding is even more pronounced in recently transmitted/founder HIV gp120 molecules, further suggesting a role for transmission. We have characterized ?4?7 on cervical CD4+ T cells and found preferential expression with CD69, CCR5, and Th17 cells. We have also shown by multiple assays that HIV preferentially replicates in ?4?7+ CD4+ T cells, and ?4?7 expression is tightly linked to both CD4 and CCR5. HIV-specific antibodies that are directed to the site where ?4?7 binds to HIV gp120 were the main correlate of protection in the RV144 vaccine trial; this was further supported by evidence for a strong sieve effect at a key residue in the ?4?7-gp120 binding epitope. More recently, in the non-human primate model, we showed that the administration of an ?4?7 targeting recombinant rhesus monoclonal antibody prior to infection protected animals from highly pathogenic low dose vaginal challenge with SIVmac251. Taken together, these data suggest that ?4?7 may help the virus identify ideal target cells in the genital mucosa, i.e. cells that are both highly activated and have potential to migrate to the gut tissue, an area rich in HIV target cells. Based on this hypothesis, in the current proposal we will test whether increased levels of ?4?7 and/or its ligands in the blood an genital mucosa are associated with increased levels of HIV acquisition and disease progression. This proposal makes use of the CAPRISA004 and 008 biorepository, which provides the statistical power and prospective study design required to determine the relevance of these markers in a real-world setting. If proven correct these data would imply that ?4?7 plays an important role in the early interaction between HIV and host mucosal immune system, and that its blockade, which is already extensively tested in the inflammatory bowel disease field, could represent a product with HIV prevention potential. Further verification of this concept in vivo could have important implications for host-directed HIV prevention strategies.